Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment o...Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.展开更多
Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefor...Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation.Methods:VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor,Ki8751,and the breast cancer cell lines,MCF-7 and MDA-MB-231,using flow cytometry,mass spectrometry,immunoblotting,and confocal microscopy.Data were analyzed using one-way analysis of variance followed by Tukey’s multiple comparison test.Results:VEGF blockade by Ki8751 significantly reduced cancer cell proliferation,and enhanced breast cancer cell apoptosis.Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins,suggesting the involvement of mitochondrial biogenesis.Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells,induced endomitosis,and arrested cancer cells in the high aneuploid phase.VEGFR2 knockdown by sh RNAs showed similar effects to those of Ki8751,confirming the specificity of Ki8751 treatment.Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species(ROS)production,which induced cancer cell apoptosis.Furthermore,Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α,and translocated PGC1αinto the nucleus.The PGC1αalterations increased mitochondrial transcription factor A(TFAM)expression and subsequently increased mitochondrial biogenesis.Conclusions:VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis,ROS production,and cell apoptosis.These findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production.展开更多
HBV is considered as a“stealth”virus that does not invoke interferon(IFN)responses;however,the mechanisms by which HBV bypasses innate immune recognition are poorly understood.In this study,we identified adenosine d...HBV is considered as a“stealth”virus that does not invoke interferon(IFN)responses;however,the mechanisms by which HBV bypasses innate immune recognition are poorly understood.In this study,we identified adenosine deaminases acting on RNA 1(ADAR1),which is a key factor in HBV evasion from IFN responses in hepatocytes.Mechanically,ADAR1 interacted with HBV RNAs and deaminated adenosine(A)to generate inosine(I),which disrupted host immune recognition and thus promoted HBV replication.Loss of ADAR1 or its deficient deaminase activity promoted IFN responses and inhibited HBV replication in hepatocytes,and blocking the IFN signaling pathways released the inhibition of HBV replication caused by ADAR1 deficiency.Notably,the HBV X protein(HBx)transcriptionally promoted ADAR1 expression to increase the threshold required to trigger intrinsic immune activation,which in turn enhanced HBV escape from immune recognition,leading to persistent infection.Supplementation with 8-azaadenosine,an ADAR1 inhibitor,efficiently enhanced liver immune activation to promote HBV clearance in vivo and in vitro.Taken together,our results delineate a molecular mechanism by which HBx promotes ADAR1-derived HBV immune escape and suggest a targeted therapeutic intervention for HBV infection.展开更多
基金supported by the China Scholarship Council(to YW)the Swedish Research Council,No.2018-02601(to MS)+7 种基金the Alzheimer Foundation,No.AF-980695(to MS)the Stockholm County Council,No.RS2020-0731(to MS)the Foundation of Old Servants(to MS)the Gun and Bertil Stohne Foundation(to MS)the?hlén Foundation,No.233055(to MS)The Swedish Fund for Research without Animal Experiments(to MS)the Swedish Dementia Foundation(to MS)the Brain foundation,No.FO2022-0131(to MS)。
文摘Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.
基金supported by grants from the Swedish HeartLung Foundation(Grant No.20160419)the Swedish Research Council+5 种基金the Swedish Foundation for International Cooperation in Research and Higher Educationthe National Natural Science Foundation of China(Grant Nos.81700110 and 8171101454)the China Scholarship CouncilKarolinska InstitutetShandong University-Karolinska Institutet Cooperative Research Fundthe Stockholm County Council。
文摘Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation.Methods:VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor,Ki8751,and the breast cancer cell lines,MCF-7 and MDA-MB-231,using flow cytometry,mass spectrometry,immunoblotting,and confocal microscopy.Data were analyzed using one-way analysis of variance followed by Tukey’s multiple comparison test.Results:VEGF blockade by Ki8751 significantly reduced cancer cell proliferation,and enhanced breast cancer cell apoptosis.Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins,suggesting the involvement of mitochondrial biogenesis.Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells,induced endomitosis,and arrested cancer cells in the high aneuploid phase.VEGFR2 knockdown by sh RNAs showed similar effects to those of Ki8751,confirming the specificity of Ki8751 treatment.Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species(ROS)production,which induced cancer cell apoptosis.Furthermore,Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α,and translocated PGC1αinto the nucleus.The PGC1αalterations increased mitochondrial transcription factor A(TFAM)expression and subsequently increased mitochondrial biogenesis.Conclusions:VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis,ROS production,and cell apoptosis.These findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production.
基金This work was supported by grants from the National Science Foundation of China(Key program 81830017,Nos.81672425 and 81902051)the National Natural Science Fund for Outstanding Youth Fund(81425012)+3 种基金Taishan Scholarship(No.tspd20181201)Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong,Key Research and Development Program of Shandong(2019GSF108238)the National Key Research and Development Program(2018YFE0126500 and 2016YFE0127000)China Mobility Grant jointly funded by the National Science Foundation of China and the Swedish Foundation for International Cooperation in Research and Higher Education(STINT),and China Postdoctoral Science Foundation(No.2018 M30782).
文摘HBV is considered as a“stealth”virus that does not invoke interferon(IFN)responses;however,the mechanisms by which HBV bypasses innate immune recognition are poorly understood.In this study,we identified adenosine deaminases acting on RNA 1(ADAR1),which is a key factor in HBV evasion from IFN responses in hepatocytes.Mechanically,ADAR1 interacted with HBV RNAs and deaminated adenosine(A)to generate inosine(I),which disrupted host immune recognition and thus promoted HBV replication.Loss of ADAR1 or its deficient deaminase activity promoted IFN responses and inhibited HBV replication in hepatocytes,and blocking the IFN signaling pathways released the inhibition of HBV replication caused by ADAR1 deficiency.Notably,the HBV X protein(HBx)transcriptionally promoted ADAR1 expression to increase the threshold required to trigger intrinsic immune activation,which in turn enhanced HBV escape from immune recognition,leading to persistent infection.Supplementation with 8-azaadenosine,an ADAR1 inhibitor,efficiently enhanced liver immune activation to promote HBV clearance in vivo and in vitro.Taken together,our results delineate a molecular mechanism by which HBx promotes ADAR1-derived HBV immune escape and suggest a targeted therapeutic intervention for HBV infection.
